Hemodialysis International 2015; 19:463–471
The effects of single hemodialysis session on arterial stiffness in hemodialysis patients ˘ ÜNÇ,1 Hakan AKDAM,1 Alper ALP,1 Fatih GENCER,2 Harun AKAR,3 Handan ÖG ˘ LU1 Yavuz YENIÇERIOG 1
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Adnan Menderes University, Aydın, Turkey; 2Department of Internal Medicine, Faculty of Medicine, Adnan Menderes University, Aydın, Turkey; 3Department of Internal Medicine Yenisehir, Tepecik Training and Research Hospital, Izmir, Turkey
Abstract Increased arterial stiffness in hemodialysis patients is a strong predictor of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) and augmentation index (AIx), which are markers of arterial stiffness, were used to determine the severity of vascular damage noninvasively. This study aimed to investigate the effects of solute volume removal and hemodynamic changes on PWV and AIx of a single hemodialysis session. Thirty hemodialysis patients were enrolled in the study. Before initiation of hemodialysis, every 15 minutes during hemodialysis, and 30 minutes after the completion of the session, measurements of PWV and AIx@75 (normalized with heart rate 75 bpm) were obtained from each patient. Body composition was analyzed by bioimpedance spectroscopy device before and 30 minutes after completion of the hemodialysis session. During the hemodialysis, no significant change was observed in AIx@75. However, PWV decreased steadily during the session reaching statistically significant level at 135th minute (P = 0.026), with a maximal drop at 210th minute (P < 0.001). At 210th minute, decrease in PWV correlated positively with the decrease in central systolic blood pressure, central diastolic blood pressure, central pulse pressure, augmentation pressure, and AIx@75. Multiple regression analysis showed that decrease in PWV at 210th minute was associated with decrease in central systolic blood pressure and central pulse pressure. Ultrafiltration during hemodialysis had no significant effect on PWV and AIx@75. Delta urea correlated positively with delta PWV at 240th minute. A significant decrease in PWV was observed during hemodialysis and correlated with urea reduction; however, we were unable to document any effect of volume removal on arterial stiffness. Key words: Augmentation index, arterial stiffness, bioimpedance, hemodialysis, pulse wave velocity
INTRODUCTION Correspondence to: H. Akdam, MD, Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Adnan Menderes University, 09100 Aydın, Turkey. E-mail: [email protected] Conflicts of interest: None.
Changes in the mechanical properties of the vessel wall, vascular calcification, volume load, inflammation, and endothelial dysfunction that develop in the large veins that accelerate atherosclerosis are common in renal failure. The cardiovascular complications associated with
© 2015 International Society for Hemodialysis DOI:10.1111/hdi.12277
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atherosclerosis are the most important causes of morbidity and mortality in patients with end-stage renal disease (ESRD).1,2 Viscoelastic features of the vessel wall determine arterial stiffness.3 The increased arterial stiffness precedes atherosclerosis and it is considered as a risk factor for atherosclerosis.4 Increased arterial stiffness results in left ventricular hypertrophy, decreased perfusion pressure in the coronary arteries, and myocardial ischemia.3,5,6 Arterial stiffness is a strong and independent predictor of cardiovascular and all-cause mortality in dialysis patients.7 Furthermore, it is also a determinant of vascular disorders such as heart failure, myocardial infarction, renal disease, stroke, and dementia.3,5 The increased arterial stiffness in chronic kidney disease can develop in association with various factors including vascular calcification, volume overload, inflammation, endothelial dysfunction, oxidative stress, sympathetic system activation, and the activation of renin-angiotensinaldosterone system.8,9 The measurements of pulse wave velocity (PWV) and augmentation index (AIx) are two major methods used to evaluate arterial stiffness and it enables noninvasive and readily measurement.10 Pulse wave velocity is the rate at which pulse wave moves down the arterial system and it increases as arterial stiffness increase.6,10,11 Volume overload results in an increased arterial stiffness by increasing the distension on the vessel wall (Laplace law).12 Some studies reported no improvement in PWV and AIx after correction of the volume load by ultrafiltration.12–14 Another study reported partial and short-term favorable effects of hemodialysis and volume control on the PWV and AIx.15 During hemodialysis, activation of the adrenergic system and renin system and production of nitric oxide were suggested to influence arterial stiffness.16–18 The aim of the present study was to evaluate the alterations and contributing factors in arterial stiffness during a single hemodialysis session in patients undergoing hemodialysis.
MATERIALS AND METHODS A total of 30 patients (16 males, 14 females) who were undergoing conventional hemodialysis for 4 hours a day and 3 days a week at least for the last 3 months were included in the study. All participants were informed of the study, and their informed consents were obtained before the study. Patients with an active infection, valvular heart disease, metallic valve, stent, metallic suture or prosthesis (due to interference with body composition mea-
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surement), coronary artery disease, peripheral artery disease, and malignancy were excluded. All patients underwent physical examination, height measurement, and weight measurement before and after dialysis. Age, gender, primary renal disease, comorbid diseases, medications, and smoking history were recorded from the patient charts.
Hemodialysis treatment The rate of blood flow was set at 350 mL/min, and flow rate of dialysate was set at 500 mL/min in measurement session. The dialysis was performed with Fresenius 4008S dialysis machine (Fresenius Medical Care AG & Co., Bad Homburg, Germany) using dialysate containing bicarbonate buffer, 1.25 mmol/L calcium, and 2 mmol/L potassium and polysulfone membrane appropriate for the body surface area. An arteriovenous fistula was used for vascular access.
Laboratory measurement The participant’s fasting blood samples were obtained for the measurements of complete blood count, serum urea, serum creatinine, serum electrolytes, bicarbonate, lipid panel, C-reactive protein (CRP), serum albumin, serum iron, ferritin, and parathyroid hormone levels before the hemodialysis session. At the end of hemodialysis session, ultrafiltration stopped and blood flow is slowed to 100 mL/min for 20 seconds, drawing samples from the arterial blood line sampling port for postdialysis serum urea, serum creatinine, and potassium measurements. Urea reduction rate (URR) was calculated as [(predialysis urea − postdialysis urea) × 100] / (predialysis urea).
Measurement of arterial stiffness Oscillometric blood pressure and arterial stiffness measurements were obtained using a single-cuffed arteriograph device (Mobil-O-Graph PWA, a model pulse wave analysis device, I.E.M. GmbH, Stolberg, Germany). The patients were instructed to avoid smoking or taking caffeinated drinks 30 minutes before the measurement. For every patient appropriate arteriograph device cuff were used and placed on the upper arm without fistula in the brachial artery tracing. After 15 minutes of rest, blood pressures and arterial stiffness measurements were started to be recorded. Before dialysis, at 15-minute intervals during dialysis session, and 30 minutes after the dialysis session, a total of 18 measurements were obtained. The device automatically inflates the pressure cuff above the systolic blood pressure to occlude brachial artery, and this
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allows the detection of pressure fluctuations in the brachial artery. Using a tonometric method, fluctuations are amplified by the precise membrane and transferred to the device. The device software separates early and late systolic and diastolic waves. Pulse wave velocity, pulse pressure (PP), and systolic and diastolic blood pressure are calculated with software using the data of central pressure changes and early (direct, P1) and late (reflected, P2) systolic and diastolic waves. The augmentation pressure (AuP) is calculated by the software as the difference between the second and first systolic peaks, and AIx is calculated as the ratio of AuP to PP. Augmentation index was normalized to a heart rate of 75 bpm (AIx@75) comparison for different heart rate.10,19,20
Body composition and volume measurement The measurement of volume load and body composition was carried out using portable bioimpedance spectroscopy device (BCM®) (Fresenius Medical Care AG & Co., Bad Homburg, Germany). Two measurements were obtained: the first 30 minutes before hemodialysis and the second 30 minutes after completion of the hemodialysis session. After entering patient’s height, weight, age, and blood pressure into the device, the electrodes were placed on the wrist and dorsum of the hand without fistula and on the ankle and dorsum of the foot at the ipsilateral side. The measurement took approximately 30 seconds. The device delivers a current at 50 different frequencies between 5 and 1000 kHz, and the measurement is based on the alteration of conductivity and insulating features of the cell membrane. The extracellular water (ECW), intracellular water (ICW), total body water (TBW), overhydration (OH), and adipose tissue mass (ATM) were composed of adipose tissue and adipose water, and lean tissue mass (LTM) was composed of fatfree mass; water can be measured using the insulating feature in low frequencies and the conductivity feature in high frequencies. The data were entered into the computer from the patient charts and analyzed using a fluid management system.21–23
Calculating delta variables during hemodialysis In the second step, the absolute change of variables during hemodialysis (delta PWV, delta AIx, delta OH, delta creatinine, etc.) was determined by calculating the difference between the values at baseline and follow-up.
Hemodialysis International 2015; 19:463–471
Statistical analysis The statistical analyses were performed using the Statistical Package for Social Sciences for Windows version 17 (SPSS Inc., Chicago, IL, USA) software package. The descriptive statistics were expressed as number (n, %) and mean ± standard deviation. The Kolmogorov-Smirnov test was used to confirm that the variables were normally distributed. Chi-square test was used for comparison of frequencies in the groups. The Mann-Whitney U test was used to compare nonparametric independent groups. The t test was used to compare normally distributed variables in dependent groups, and analysis of variance (ANOVA) was used in repeated measurements. To compare dependent variables that did not show normal distribution, the Friedman ANOVA test was used. Multiple regression analysis was used to determine the factors affecting AIx and PWV variables. Normally distributed variable interactions were analyzed by Pearson’s correlation coefficient, and variables that do not meet the normal distribution were analyzed by Spearman’s correlation coefficient. A P value 0.005).
Figure 2 Pulse wave velocity (PWV) changes during hemodialysis session. (*Significant difference reached at 135 minutes, P = 0.026; ƒThe most significant difference was observed at 210 minutes, P < 0.001.)
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Figure 3 Correlation between pulse wave velocity (PWV) with the other variables. CDBP = central diastolic blood pressure; CSBP = central systolic blood pressure.
changes. The measurements obtained at 15-minute intervals showed a significant decrease in PWV that started at 135 minutes during hemodialysis and continued until 30 minutes after the end of the dialysis. The changes in PWV were found to be correlated with delta CSBP, delta CPP, delta AuP, and delta AIx. The decreases in CSBP and CPP are independent factors affecting delta PWV. In the present study, ultrafiltration performed during dialysis session had no effect on PWV, which was consistent with certain publications in the literature. Blacker et al.2 reported that even if dry weight and blood pressure were controlled in the long-term follow-up of hemodialysis patients, this did not always result in a decrease in PWV. Some other studies also did not report improvement
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in PWV, AIx, or arterial compliance after correction of the volume load with ultrafiltration.12–14 It was found that although volume control provided an arithmetic decrease in PWV, volume control alone did not have an impact on aortic PWV, but they highlighted that a significant reduction in PWV was noted in patients who simultaneously received therapy with angiotensin-converting enzyme inhibitors.9 This can be explained by further aggravation of already stimulated adrenergic activity by fluid withdrawal in patients with ESRD and alleviation of this overactivity by the inhibition of angiotensin-converting enzyme. In addition, the renin system that is activated during ultrafiltration also contributes by causing an acute impairment in the elasticity of the large arteries.16,17
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Figure 4 Effects of hemodialysis session on body composition. ATM = adipose tissue mass; BCM = body cell mass; ECW = extracellular water; ICW = intracellular water; LTM = lean tissue mass; TBW = total body water. * = difference between pre- and postdialysis ECW, P < 0.001; ƒ = difference between pre- and postdialysis TBW, P < 0.001.
Another study reported that the improvement in PWV and arterial stiffness was transient with volume and salt control and did not change endothelial functions.15 An improvement in endothelial functions and a decrease in PWV were detected as a result of an increased clearance of endogenous nitric oxide synthetase inhibitor asymmetric dimethylarginine with dialysis.18 Similarly, the decrease in asymmetric dimethylarginine levels after hemodialysis was found to be associated with the improvement in central arterial pressure wave and that nitric oxide might have a role in regulating arterial stiffness.25 However, Kosch et al.1 did not support this notion. They reported an increase in systemic nitric oxide concentration during hemodialysis session in dialysis patients, which, however, returned to baseline levels after dialysis session. They concluded that hemodialysis therapy and volume control had partial and short-term favorable effects on the increased PWV, AIx, and arterial stiffness.15 They also reported that PWV in hemodialysis patients underwent cyclic changes in a period of 1 week; PWV, hydration status, and blood pressure decreased during dialysis therapy and increased during the interdialytic period.24 The results of daily hemodialysis therapy for 1 week and 8-hour hemodialysis overnight for 1-year studies reported improvements in PWV and AIx when compared with conventional hemodialysis.26,27 These results suggested that better uremic clearance and better volume control produced favorable outcomes in the arterial stiffness. In the present study, PWV, fluid overload, serum urea, and systolic blood pressure decreased after hemodialysis, and a strong correlation existed between
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PWV decrease with urea reduction and decrease in systolic blood pressure; however, there was no significant correlation between PWV changes with ultrafiltration. These results suggest that, central hemodynamics and urea clearance have a critical role on acute regulation of arterial stiffness in hemodialysis patients. Progression of arterial stiffness in hemodialysis patients has been reported in a longitudinal study, and pointed a significant association between advanced glycation end product (pentosidine) levels and progression of carotid femoral PWV.28 Our study focuses on acute change of PWV during a single hemodialysis session and it seems that central hemodynamic changes effected PWV independent from ultrafiltration. In Mardare et al.’s14 study, a significant decrease in AIx was reported to occur in the first 2 hours of dialysis. This decrease was associated with systolic blood pressure and PP, and the changes in systolic blood pressure appeared as the most important factor affecting the changes in AIx. In the present study, AIx that is stated as the measure of reflected wave velocity showed a nonlinear distribution and did not show statistically significant changes during the dialysis session. The present study was consistent with the literature data suggesting that volume reduction with ultrafiltration showed no effect on AIx.12,13 This was considered to be related to vasoconstriction and increased angiotensin II release due to stimulation of reninangiotensin-aldosterone system by the volume correction during dialysis.12–14 The study that showed more remarkable decrease in the AIx in patients using angiotensinconverting enzyme inhibitors supported this notion.9 Compared with males, AIx before dialysis was significantly higher in female patients. This suggested that the fat tissue index, which was significantly higher in females than in males (P = 0.033), had an effect on the development of atherosclerosis. The AIx is the ratio of AuP to the PP. In the elderly, AuP increases in tandem with PP, and therefore AIx is not a good marker of arterial stiffness particularly in patients aged above 55 years.29 The Framingham study also found similar results in patients aged above 50 years.30 In the present study, delta PWV showed a correlation in the same direction with delta AuP and delta CPP. Due to the fact that AuP and CPP showed changes in the same direction during hemodialysis sessions and high mean age of the study patients, it was considered that no changes occurred in AIx. In the present study, diabetic patients’ rate was lower in contrast to worldwide hemodialysis population. Cardiovascular disease is often developing in diabetic patients in the predialysis stage and more common than nondiabetic in ESRD,31 and we excluded from the study who have
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cardiovascular disease history. So, we thought that the lower rate is due to exclusion criteria of study. In conclusion, PWV decreased during hemodialysis session, and delta CSBP and delta PP were the determinants of this change. The correction of volume with ultrafiltration had no effect on the decrease in PWV. Studies investigating the potential role of nitric oxide, asymmetric dimethylarginine, endothelin, renin, and angiotensin metabolism in the etiology are required. Manuscript received October 2014; revised December 2014.
REFERENCES 1 Kosch M, Levers A, Barenbrock M, et al. Acute effects of hemodialysis on endothelial function and large artery elasticity. Nephrol Dial Transplant. 2001; 16:1663–1668. 2 Blacher J, Guerin AP, Pannier B, London GM. Arterial calcifications, arterial stiffness and cardiovascular risk in end-stage renal disease. Hypertension. 2001; 38:938–942. 3 Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999; 99:2434– 2439. 4 Davies JI, Struthers AD. Pulse wave analysis and pulse wave velocity: A critical review of their strengths and weaknesses. J Hypertens. 2003; 21:463–472. 5 Covic A, Mardare N, Tatomir PG, Prisada O, Goldsmith JA. Arterial wave reflections and mortality in haemodialysis patients-only relevant in elderly cardiovascularly compromised? Nephrol Dial Transplant. 2006; 21:2859– 2866. 6 Kanbay M, Afsar B, Gusbeth-Tatomir P, Covic A. Arterial stiffness in dialysis patients: Where are we now? Int Urol Nephrol. 2010; 42:741–752. 7 Pannier B, Guerin AP, Marchais SJ, Safar ME, London GM. Stiffness of capacitive and conduit arteries prognostic significance for end-stage renal disease patients. Hypertension. 2005; 45:592–596. 8 Tatomir GP, Covic A. Causes and consequences of increased arterial stiffness in chronic kidney disease patients. Kidney Blood Press Res. 2007; 30:97–107. 9 Vuurmans JLT, Boer WH, Bos WJW, Blankestijn PJ, Koomans HA. Contribution of volume overload and angiotensin II to the increased pulse wave velocity of hemodialysis patients. J Am Soc Nephrol. 2002; 13:177– 183. 10 Shirwany NA, Zou M. Arterial stiffness: A brief review. Acta Pharmacol Sin. 2010; 31:1267–1276. 11 Mackenzie IS, Wilkinson IB, Cockcroft JR. Assessment of arterial stiffness in clinical practice. QJM. 2002; 95:67– 74.
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12 Barenbrock M, Spieker C, Laske V, et al. Studies of the vessel wall properties in hemodialysis patients. Kidney Int. 1994; 45:1397–1400. 13 Marchais S, Guerin A, Safar M, London G. Arterial compliance in uremia. J Hypertens. 1989; 7:84– 85. 14 Mardare NG, Goldsmith DJA, Tatomir GP, Covic A. Intradialytic changes in reflective properties of the arterial system during a single hemodialysis session. Hemodial Int. 2005; 9:376–382. 15 Hogas S, Ardeleanu S, Segall L, et al. Changes in arterial stiffness following dialysis in relation to overhydration and to endothelial function. Int Urol Nephrol. 2012; 44:897–905. 16 Converse RL, Jacobson TN, Toto RD, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992; 327:1912–1918. 17 Ligtenberg G, Blankestijn PJ, Oey PL, et al. Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med. 1999; 340:1321– 1328. 18 Nishiura N, Kita T, Yamada K, et al. Radial augmentation index is related to cardiovascular risk in hemodialysis patients. Ther Apher Dial. 2008; 12:157–163. 19 Horváth IG, Németh A, Lenkey Z, et al. Invasive validation of a new oscillometric device (arteriograph) for measuring augmentation index, central blood pressure and aortic pulse wave velocity. J Hypertens. 2010; 28:2068– 2075. 20 Jatoi NA, Mahmud A, Bennett K, Feely J. Assessment of arterial stiffness in hypertension: Comparison of oscillometric (Arteriograph), piezoelectronic (Complior) and tonometric (SphygmoCor) techniques. J Hypertens. 2009; 27:2186–2191. 21 Moissl UM, Wabel P, Chamney PW, et al. Body fluid volume determination via body composition spectroscopy in health and disease. Physiol Meas. 2006; 27:921– 933. 22 De Lorenzo A, Andreoli A, Matthie J, Withers P. Predicting body cell mass with bioimpedance by using theoretical methods: A technological review. J Appl Physiol. 1997; 82:1542–1558. 23 Van Biesen W, Williams JD, Covic AC, EuroBCM Study Group, et al. Fluid status in peritoneal dialysis patients: The European Body Composition Monitoring (EuroBCM) study cohort. PLoS ONE. 2011; 6:e17148. 24 Di Iorio B, Nazzaro P, Cucciniello E, Bellizzi V. Influence of haemodialysis on variability of pulse wave velocity in chronic haemodialysis patients. Nephrol Dial Transplant. 2010; 25:1579–1583. 25 Soveri I, Lind L, Wikström B, Zilmer M, Zilmer K, Fellström B. Improvement in central arterial pressure waveform during hemodialysis is related to a reduction in Asymmetric Dimethylarginine (ADMA) Levels. Nephron Clin Pract. 2007; 106:180–186.
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26 Demirci MS, Celik G, Ozkahya M, et al. Effects of thrice weekly nocturnal hemodialysis on arterial stiffness. Atherosclerosis. 2012; 220:477–485. 27 Di Micco L, Torraca S, Sirico ML, Tartaglia D, Di Iorio B. Daily dialysis reduces pulse wave velocity in chronic hemodialysis patients. Hypertens Res. 2012; 35:518–522. 28 Utescu MS, Couture V, Mac-Way F, et al. Determinants of progression of aortic stiffness in hemodialysis patients: A prospective longitudinal study. Hypertension. 2013; 62:154–160.
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29 Fantin F, Mattocks A, Bulpitt CJ, Banya W, Rajkumar C. Is augmentation index a good measure of vascular stiffness in the elderly? Age Ageing. 2007; 36:43–48. 30 Mitchell GF, Parise H, Benjamin EJ, et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: The Framingham Heart Study. Hypertension. 2004; 43:1239–1245. 31 Locatelli F, Pozzoni P, Del Vecchio L. Renal replacement therapy in patients with diabetes and end-stage renal disease. J Am Soc Nephrol. 2004; 15(Suppl 1):25–29.
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The effects of single hemodialysis session on arterial stiffness in hemodialysis patients ˘ ÜNÇ,1 Hakan AKDAM,1 Alper ALP,1 Fatih GENCER,2 Harun AKAR,3 Handan ÖG ˘ LU1 Yavuz YENIÇERIOG 1
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Adnan Menderes University, Aydın, Turkey; 2Department of Internal Medicine, Faculty of Medicine, Adnan Menderes University, Aydın, Turkey; 3Department of Internal Medicine Yenisehir, Tepecik Training and Research Hospital, Izmir, Turkey
Abstract Increased arterial stiffness in hemodialysis patients is a strong predictor of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) and augmentation index (AIx), which are markers of arterial stiffness, were used to determine the severity of vascular damage noninvasively. This study aimed to investigate the effects of solute volume removal and hemodynamic changes on PWV and AIx of a single hemodialysis session. Thirty hemodialysis patients were enrolled in the study. Before initiation of hemodialysis, every 15 minutes during hemodialysis, and 30 minutes after the completion of the session, measurements of PWV and AIx@75 (normalized with heart rate 75 bpm) were obtained from each patient. Body composition was analyzed by bioimpedance spectroscopy device before and 30 minutes after completion of the hemodialysis session. During the hemodialysis, no significant change was observed in AIx@75. However, PWV decreased steadily during the session reaching statistically significant level at 135th minute (P = 0.026), with a maximal drop at 210th minute (P < 0.001). At 210th minute, decrease in PWV correlated positively with the decrease in central systolic blood pressure, central diastolic blood pressure, central pulse pressure, augmentation pressure, and AIx@75. Multiple regression analysis showed that decrease in PWV at 210th minute was associated with decrease in central systolic blood pressure and central pulse pressure. Ultrafiltration during hemodialysis had no significant effect on PWV and AIx@75. Delta urea correlated positively with delta PWV at 240th minute. A significant decrease in PWV was observed during hemodialysis and correlated with urea reduction; however, we were unable to document any effect of volume removal on arterial stiffness. Key words: Augmentation index, arterial stiffness, bioimpedance, hemodialysis, pulse wave velocity
INTRODUCTION Correspondence to: H. Akdam, MD, Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Adnan Menderes University, 09100 Aydın, Turkey. E-mail: [email protected] Conflicts of interest: None.
Changes in the mechanical properties of the vessel wall, vascular calcification, volume load, inflammation, and endothelial dysfunction that develop in the large veins that accelerate atherosclerosis are common in renal failure. The cardiovascular complications associated with
© 2015 International Society for Hemodialysis DOI:10.1111/hdi.12277
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Ög˘ünç et al.
atherosclerosis are the most important causes of morbidity and mortality in patients with end-stage renal disease (ESRD).1,2 Viscoelastic features of the vessel wall determine arterial stiffness.3 The increased arterial stiffness precedes atherosclerosis and it is considered as a risk factor for atherosclerosis.4 Increased arterial stiffness results in left ventricular hypertrophy, decreased perfusion pressure in the coronary arteries, and myocardial ischemia.3,5,6 Arterial stiffness is a strong and independent predictor of cardiovascular and all-cause mortality in dialysis patients.7 Furthermore, it is also a determinant of vascular disorders such as heart failure, myocardial infarction, renal disease, stroke, and dementia.3,5 The increased arterial stiffness in chronic kidney disease can develop in association with various factors including vascular calcification, volume overload, inflammation, endothelial dysfunction, oxidative stress, sympathetic system activation, and the activation of renin-angiotensinaldosterone system.8,9 The measurements of pulse wave velocity (PWV) and augmentation index (AIx) are two major methods used to evaluate arterial stiffness and it enables noninvasive and readily measurement.10 Pulse wave velocity is the rate at which pulse wave moves down the arterial system and it increases as arterial stiffness increase.6,10,11 Volume overload results in an increased arterial stiffness by increasing the distension on the vessel wall (Laplace law).12 Some studies reported no improvement in PWV and AIx after correction of the volume load by ultrafiltration.12–14 Another study reported partial and short-term favorable effects of hemodialysis and volume control on the PWV and AIx.15 During hemodialysis, activation of the adrenergic system and renin system and production of nitric oxide were suggested to influence arterial stiffness.16–18 The aim of the present study was to evaluate the alterations and contributing factors in arterial stiffness during a single hemodialysis session in patients undergoing hemodialysis.
MATERIALS AND METHODS A total of 30 patients (16 males, 14 females) who were undergoing conventional hemodialysis for 4 hours a day and 3 days a week at least for the last 3 months were included in the study. All participants were informed of the study, and their informed consents were obtained before the study. Patients with an active infection, valvular heart disease, metallic valve, stent, metallic suture or prosthesis (due to interference with body composition mea-
464
surement), coronary artery disease, peripheral artery disease, and malignancy were excluded. All patients underwent physical examination, height measurement, and weight measurement before and after dialysis. Age, gender, primary renal disease, comorbid diseases, medications, and smoking history were recorded from the patient charts.
Hemodialysis treatment The rate of blood flow was set at 350 mL/min, and flow rate of dialysate was set at 500 mL/min in measurement session. The dialysis was performed with Fresenius 4008S dialysis machine (Fresenius Medical Care AG & Co., Bad Homburg, Germany) using dialysate containing bicarbonate buffer, 1.25 mmol/L calcium, and 2 mmol/L potassium and polysulfone membrane appropriate for the body surface area. An arteriovenous fistula was used for vascular access.
Laboratory measurement The participant’s fasting blood samples were obtained for the measurements of complete blood count, serum urea, serum creatinine, serum electrolytes, bicarbonate, lipid panel, C-reactive protein (CRP), serum albumin, serum iron, ferritin, and parathyroid hormone levels before the hemodialysis session. At the end of hemodialysis session, ultrafiltration stopped and blood flow is slowed to 100 mL/min for 20 seconds, drawing samples from the arterial blood line sampling port for postdialysis serum urea, serum creatinine, and potassium measurements. Urea reduction rate (URR) was calculated as [(predialysis urea − postdialysis urea) × 100] / (predialysis urea).
Measurement of arterial stiffness Oscillometric blood pressure and arterial stiffness measurements were obtained using a single-cuffed arteriograph device (Mobil-O-Graph PWA, a model pulse wave analysis device, I.E.M. GmbH, Stolberg, Germany). The patients were instructed to avoid smoking or taking caffeinated drinks 30 minutes before the measurement. For every patient appropriate arteriograph device cuff were used and placed on the upper arm without fistula in the brachial artery tracing. After 15 minutes of rest, blood pressures and arterial stiffness measurements were started to be recorded. Before dialysis, at 15-minute intervals during dialysis session, and 30 minutes after the dialysis session, a total of 18 measurements were obtained. The device automatically inflates the pressure cuff above the systolic blood pressure to occlude brachial artery, and this
Hemodialysis International 2015; 19:463–471
Arterial stiffness changes in dialysis
allows the detection of pressure fluctuations in the brachial artery. Using a tonometric method, fluctuations are amplified by the precise membrane and transferred to the device. The device software separates early and late systolic and diastolic waves. Pulse wave velocity, pulse pressure (PP), and systolic and diastolic blood pressure are calculated with software using the data of central pressure changes and early (direct, P1) and late (reflected, P2) systolic and diastolic waves. The augmentation pressure (AuP) is calculated by the software as the difference between the second and first systolic peaks, and AIx is calculated as the ratio of AuP to PP. Augmentation index was normalized to a heart rate of 75 bpm (AIx@75) comparison for different heart rate.10,19,20
Body composition and volume measurement The measurement of volume load and body composition was carried out using portable bioimpedance spectroscopy device (BCM®) (Fresenius Medical Care AG & Co., Bad Homburg, Germany). Two measurements were obtained: the first 30 minutes before hemodialysis and the second 30 minutes after completion of the hemodialysis session. After entering patient’s height, weight, age, and blood pressure into the device, the electrodes were placed on the wrist and dorsum of the hand without fistula and on the ankle and dorsum of the foot at the ipsilateral side. The measurement took approximately 30 seconds. The device delivers a current at 50 different frequencies between 5 and 1000 kHz, and the measurement is based on the alteration of conductivity and insulating features of the cell membrane. The extracellular water (ECW), intracellular water (ICW), total body water (TBW), overhydration (OH), and adipose tissue mass (ATM) were composed of adipose tissue and adipose water, and lean tissue mass (LTM) was composed of fatfree mass; water can be measured using the insulating feature in low frequencies and the conductivity feature in high frequencies. The data were entered into the computer from the patient charts and analyzed using a fluid management system.21–23
Calculating delta variables during hemodialysis In the second step, the absolute change of variables during hemodialysis (delta PWV, delta AIx, delta OH, delta creatinine, etc.) was determined by calculating the difference between the values at baseline and follow-up.
Hemodialysis International 2015; 19:463–471
Statistical analysis The statistical analyses were performed using the Statistical Package for Social Sciences for Windows version 17 (SPSS Inc., Chicago, IL, USA) software package. The descriptive statistics were expressed as number (n, %) and mean ± standard deviation. The Kolmogorov-Smirnov test was used to confirm that the variables were normally distributed. Chi-square test was used for comparison of frequencies in the groups. The Mann-Whitney U test was used to compare nonparametric independent groups. The t test was used to compare normally distributed variables in dependent groups, and analysis of variance (ANOVA) was used in repeated measurements. To compare dependent variables that did not show normal distribution, the Friedman ANOVA test was used. Multiple regression analysis was used to determine the factors affecting AIx and PWV variables. Normally distributed variable interactions were analyzed by Pearson’s correlation coefficient, and variables that do not meet the normal distribution were analyzed by Spearman’s correlation coefficient. A P value 0.005).
Figure 2 Pulse wave velocity (PWV) changes during hemodialysis session. (*Significant difference reached at 135 minutes, P = 0.026; ƒThe most significant difference was observed at 210 minutes, P < 0.001.)
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Figure 3 Correlation between pulse wave velocity (PWV) with the other variables. CDBP = central diastolic blood pressure; CSBP = central systolic blood pressure.
changes. The measurements obtained at 15-minute intervals showed a significant decrease in PWV that started at 135 minutes during hemodialysis and continued until 30 minutes after the end of the dialysis. The changes in PWV were found to be correlated with delta CSBP, delta CPP, delta AuP, and delta AIx. The decreases in CSBP and CPP are independent factors affecting delta PWV. In the present study, ultrafiltration performed during dialysis session had no effect on PWV, which was consistent with certain publications in the literature. Blacker et al.2 reported that even if dry weight and blood pressure were controlled in the long-term follow-up of hemodialysis patients, this did not always result in a decrease in PWV. Some other studies also did not report improvement
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in PWV, AIx, or arterial compliance after correction of the volume load with ultrafiltration.12–14 It was found that although volume control provided an arithmetic decrease in PWV, volume control alone did not have an impact on aortic PWV, but they highlighted that a significant reduction in PWV was noted in patients who simultaneously received therapy with angiotensin-converting enzyme inhibitors.9 This can be explained by further aggravation of already stimulated adrenergic activity by fluid withdrawal in patients with ESRD and alleviation of this overactivity by the inhibition of angiotensin-converting enzyme. In addition, the renin system that is activated during ultrafiltration also contributes by causing an acute impairment in the elasticity of the large arteries.16,17
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Figure 4 Effects of hemodialysis session on body composition. ATM = adipose tissue mass; BCM = body cell mass; ECW = extracellular water; ICW = intracellular water; LTM = lean tissue mass; TBW = total body water. * = difference between pre- and postdialysis ECW, P < 0.001; ƒ = difference between pre- and postdialysis TBW, P < 0.001.
Another study reported that the improvement in PWV and arterial stiffness was transient with volume and salt control and did not change endothelial functions.15 An improvement in endothelial functions and a decrease in PWV were detected as a result of an increased clearance of endogenous nitric oxide synthetase inhibitor asymmetric dimethylarginine with dialysis.18 Similarly, the decrease in asymmetric dimethylarginine levels after hemodialysis was found to be associated with the improvement in central arterial pressure wave and that nitric oxide might have a role in regulating arterial stiffness.25 However, Kosch et al.1 did not support this notion. They reported an increase in systemic nitric oxide concentration during hemodialysis session in dialysis patients, which, however, returned to baseline levels after dialysis session. They concluded that hemodialysis therapy and volume control had partial and short-term favorable effects on the increased PWV, AIx, and arterial stiffness.15 They also reported that PWV in hemodialysis patients underwent cyclic changes in a period of 1 week; PWV, hydration status, and blood pressure decreased during dialysis therapy and increased during the interdialytic period.24 The results of daily hemodialysis therapy for 1 week and 8-hour hemodialysis overnight for 1-year studies reported improvements in PWV and AIx when compared with conventional hemodialysis.26,27 These results suggested that better uremic clearance and better volume control produced favorable outcomes in the arterial stiffness. In the present study, PWV, fluid overload, serum urea, and systolic blood pressure decreased after hemodialysis, and a strong correlation existed between
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PWV decrease with urea reduction and decrease in systolic blood pressure; however, there was no significant correlation between PWV changes with ultrafiltration. These results suggest that, central hemodynamics and urea clearance have a critical role on acute regulation of arterial stiffness in hemodialysis patients. Progression of arterial stiffness in hemodialysis patients has been reported in a longitudinal study, and pointed a significant association between advanced glycation end product (pentosidine) levels and progression of carotid femoral PWV.28 Our study focuses on acute change of PWV during a single hemodialysis session and it seems that central hemodynamic changes effected PWV independent from ultrafiltration. In Mardare et al.’s14 study, a significant decrease in AIx was reported to occur in the first 2 hours of dialysis. This decrease was associated with systolic blood pressure and PP, and the changes in systolic blood pressure appeared as the most important factor affecting the changes in AIx. In the present study, AIx that is stated as the measure of reflected wave velocity showed a nonlinear distribution and did not show statistically significant changes during the dialysis session. The present study was consistent with the literature data suggesting that volume reduction with ultrafiltration showed no effect on AIx.12,13 This was considered to be related to vasoconstriction and increased angiotensin II release due to stimulation of reninangiotensin-aldosterone system by the volume correction during dialysis.12–14 The study that showed more remarkable decrease in the AIx in patients using angiotensinconverting enzyme inhibitors supported this notion.9 Compared with males, AIx before dialysis was significantly higher in female patients. This suggested that the fat tissue index, which was significantly higher in females than in males (P = 0.033), had an effect on the development of atherosclerosis. The AIx is the ratio of AuP to the PP. In the elderly, AuP increases in tandem with PP, and therefore AIx is not a good marker of arterial stiffness particularly in patients aged above 55 years.29 The Framingham study also found similar results in patients aged above 50 years.30 In the present study, delta PWV showed a correlation in the same direction with delta AuP and delta CPP. Due to the fact that AuP and CPP showed changes in the same direction during hemodialysis sessions and high mean age of the study patients, it was considered that no changes occurred in AIx. In the present study, diabetic patients’ rate was lower in contrast to worldwide hemodialysis population. Cardiovascular disease is often developing in diabetic patients in the predialysis stage and more common than nondiabetic in ESRD,31 and we excluded from the study who have
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cardiovascular disease history. So, we thought that the lower rate is due to exclusion criteria of study. In conclusion, PWV decreased during hemodialysis session, and delta CSBP and delta PP were the determinants of this change. The correction of volume with ultrafiltration had no effect on the decrease in PWV. Studies investigating the potential role of nitric oxide, asymmetric dimethylarginine, endothelin, renin, and angiotensin metabolism in the etiology are required. Manuscript received October 2014; revised December 2014.
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